LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice

Abstract

Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXRα binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.

Cytotoxic Minor Piericidin Derivatives from the Actinomycete Strain Streptomyces psammoticus SCSIO NS126

“…It is suggested that a carbonylated branched chain could greatly enhance the cytotoxicity of the piericidin analogs. The new piericidin glycoside 8 has a broad spectrum of cytotoxic activity, and it also confirmed that piericidin glycosides possess the potential for further development as antitumor agents [5,6]. This study advances our comprehensive understanding of the structural diversity and cytotoxicity of actinomycete-derived piericidin compounds.…”

“…Strain NS126 was further fermented at a 300 L scale under optimized fermentation conditions (pH 4, cultured for 30 h). About 1200 mg PA and 680 mg GPA were isolated and purified in order to further evaluate their pharmacological and pharmacokinetic/toxicokinetic properties [5]. In addition to the accumulation of the reported active piericidins, eight other new piericidins (1-8) were obtained in trace amounts (about 1-3 mg), as well as a known glucopireicidin B (9) that was discoved first in this strain [12] (Figure 1).…”

“…In a culture extract of the strain Streptomyces psammoticus SCSIO NS126, twenty-seven natural piericidins were isolated and found to have notable anti-renal cell carcinoma (RCC) activities. Our previous studies also revealed that piericidins could conceivably provide a novel scaffold for the further development of potent and mechanistically novel anti-RCC agents [5,6]. It was previously shown that external pH plays an important role in regulating the secondary metabolites of microorganisms [8].…”

“…Recently, some biologically significant piericidins were discovered in two mangrovesediment-derived Streptomyces strains by our group [5][6][7]. In a culture extract of the strain Streptomyces psammoticus SCSIO NS126, twenty-seven natural piericidins were isolated and found to have notable anti-renal cell carcinoma (RCC) activities.…”

Natural Products Targeting Liver X Receptors or Farnesoid X Receptor

“…Further study demonstrated that PA/GPA aggravated hepatotoxicity in high cholesterol diet-fed LXRα-activated mice while exhibiting no toxicity in chow diet-fed mice, indicating that the accumulation as well as the delay metabolism process of cholesterol resulted in hepatotoxicity and cholestasis. Pharmacokinetic study discovered that GPA existed as a prodrug in the liver and exerted toxic effect due to transforming into PA, different from PA directly combined with LXRα as an inhibitor ( Zhou et al, 2019 ; Liang et al, 2020 ).…”